Ethanoanthracene amines



United States Patent Ofitice 3,377,353 Patented Apr. 9, 1968 3,377,353ETHANOANTHRACENE AMINES William F. Bruce, Havertown, Pa., assignor toAmerican Home Products Corporation, New York, N.Y., a corporation ofDelaware No Drawing. Filed May 26, 1964, Ser. No. 370,368 14 Claims.(Cl. 260-294) wherein B is hydrogen, amino, or nitro; R and R' arehydrogen or lower alkyl; E is selected from the group consisting ofdialkylaminophenyl, Z-pyndyl, 3-pyridyl, dialkyl-2-pyridyl,halo-2-pyridyl, Z-pyridylmethyl, dialkoxyphenethyl, triazolyl,3-piperidyl, piperidino, lower alkynyl, amino and guanidino; and thequaternary ammonium salts with (lower)alkyl, (lower)alkenyl and(loWer)alkynyl halides and sulfates.

In the synthesis of the compounds of the invention, an ethanoanthraceneanhydride (1) and an amine of the formula ENH where E is as previouslydefined, are dissolved in an inert solvent such as dimethylformamidegiving rise 'to a spontaneous reaction and solution. After heating for ashort time to around 80 C., the solution is poured into water and aproduct of Formula (II) is recovered. This product can be quaternizedreadily with alkyl halides, alkyl sulfates, alkenyl halides and alkynylhalides.

To produce a quaternary ammonium salt of a com-' pound of Formula III, acompound of Formula ZX,

Where Z is lower alkyl, lower alkenyl or alkynyl and X 1s halide orsulfate, is dissolved with a compound of Formula II in an inert solventsuch as toluene, benzene, chloroform, ether or acetonitrile. Theresulting reaction mixture is then warmed to around 80 C. until aprecipitate appears. This precipitate is filtered and recrystallized togive the desired quaternized product.

The reactions occurring in the preparation of the claimed compounds areillustrated below:

' impurities, the filtrate I ENH: R 0-0 0 B B \YE o-oo R A t g B BN-EZ-X- I I n -04 (III) The starting ethanoanthracene anhydride (I) canbe prepared as described in JACS 60, 481, by heating anthracene or asubstituted anthracene with maleic anhydride or an alkyhnaleic anhydridein benzene under Diels-Alder Reaction conditions. The preparation ofalkylmaleic anhydrides is given in J. Org. Chem. 81, 673 (1956).

Where the starting ethanoanthracene anhydride is not functionallysubstituted; i.e., Where B is hydrogen; the product of Formula II can benitrated with fuming nitric acid to produce the corresponding productwhere either or both of the su-b-stituents B (depending on the amount ofnitric acid used) is N0 The nitro compound thus obtained can have itsnitro function reduced to amino by hydrogenating in the presence of acatalytic amount of palladium on charcoal. I

The following examples are intended to illustrate but not to limit theinvention. For the sake of conciseness, the various examples are groupedaccording to Formulas II and III (above) with the various symbols beingas defined for the respective formulas.

The synthesis of a representative compound listed in Table I (Example 8)is the following:

To a suspension of 14 g. of 9,10-dihydro-9,10-ethanoanthracene-'11,12-dicarboxylic' anhydride in 50 ml. of di=methylformamide is added 6.5 g. of N ethyl-3-amino piperidine. Themixture is shaken and the solid gradually dissolves with evolution ofheat. After filtering out dark is diluted with five volumes of water togive a white viscous oil. Upon being rubbed with a glass rod,thisvbecomes solid Within an hour and can be filtered and recrystallizedfrom methyl ethyl ketone to give 18 g. ofN-(1-ethyl-3-piperidyl-9,10-dihydro-9,10- ethanoanthracene-11,12-dicarboxylic acid imide melting at -6".

The synthesis of a representative compound listed in Table II (Example18) is the followin A solution of 10 g. of N-3-piperidyl-9,l0dihydro-9,l0- ethanoanthracene-'11,12-dicarboxylic acid imide in 15 ml,of hot toluene is mixed with 5 ml. of crotyl bromide and the solution isheated on a steam bath for four hours. A white precipitate soon appearsand gradually fills the flask. After cooling, filtering andcrystallizing from ethanol, one obtains -5 g. of l'-(2butenyl)-1'-ethyl-3 (9, 10 dihyd-ro 9,10 ethanoanthracene 11, 12dicarboximido)-piperidinium bromide hemihydrate, melting at 295-6.

of the type of the type formamide.

TABLE L[ICntinued A M.P., EZ X R Formula. Activity Ex. O. 4

19. Diethyllp-(Q,10-dihydro-9,10- 810d. NEt Me I MeSO4 I HCl0HI|NIOds-%H2O Hypotensive ethanoanthracene-1l,12- -%H,OH depressant.dicarboxlmido)phenyl] methylammonium methosulfate.

1-allyl-2-(9,10-dihydro-9,10- 210-11 CH, Br-%Hg0 H CnHnBrN OM QLODepressant.

ethanoanthracene-11,l2- N- dicarboxlmidomethyl) I pyrrdmrum bromide. CHCH=CHa The following examples illustrate the preparation of teredorally, larger amounts thereof are required to proadditional compoundscomprehended within the present duce the same eiTect as a smaller amountgiven inventive scope: parenterally.

Example 19 2 The present invention also includes the process of bringingthe compounds thereof into a form suitable for PreparationofN-am1no-2-nitro-9-ethyl-9,10-d1hydrotherapeutic administration byassociating them with9,lO-ethanoanthracene-ld-n-propyl-11,12-dicarbox1m1de liquid or solid,pharmaceutically acceptable carriers.

What is claimed is: (1) Preparation of N-am1no-9-ethyl-9,10-d1hydro-9, 1A compound represented by the formula: IO-ethanoanthracene-ll-n-propyl11,12-dicar-box1mrde:

(A) 9,10 ethy1-9,10-dihydro-9,IO-ethanoanthracened1-n- R Opropyl-l1,12-dicarboxylic anhydride: A solution of 0.1 H

mol. of 9-ethylanthracene and 1 mol. of n-propyl succinic anhydride in500 ml. of benzene is heated overnight on a steam bath. Uponconcentrating and cooling, the prod- B I B uct crystallizes and iscollected on a filter. (B) A solution of the product from A in 100 ml.of dimethyll formamide and 0.1 mol. of hydrazine hydrate is heated C Oovernight on a steam bath. Upon dilution with cold water, g

N-amino-9-ethyl-9,10 dihyd*ro-9,10 ethanoanthracene-1l-n-propyi-11,12-dicarboximide separates and is collected on a filter.It is recrystallized from dimethylwherein B is selected from the groupconsisting of hydrogen, amino and nitro, R and 'R' are selected from thegroup consisting of hydrogen and lower alkyl and E is selected from thegroup consisting of: di(lower)alky1- aminophenyl,di(lower)alkyl-2-pyridyl, Z-pyridylmethyl, halo-2-pyridyl, triazolyl,3-piperidyl, piperidino, lower alkynyl, amino, di(lower)alkoxyphenethyland quanidino;

(2) To a solution at room temperature of 0.1 mole of N-amino-9-ethyl9,10-dihydro-9,l0 ethanoanthracene- 11-n-propyl-11,12-dicarboximideprepared as above in 150 ml. of concentrated nitric acid, is addeddropwise with Surfing 10 of red fummg acld' The temand the qua-ternaryammonium salts thereof with (lower) a 1 es.

is poured on 1 kg. of ice and is made alkaline by the addition of 10%sodium hydroxide. This causes separation i gg f g ffi i igigiggggw'dlhydro of the product whlch can be recrystallized from ethanol. 3dimethylaminophenyvn 9,10 dihydro 9)10ethanoanthracene-l1,12-dicarboximide.

Example 20 4. 9,10 dihydroN-(4,6 dimethyl-2-pyridyl) 9,10- Preparationof N-amino-2-amino-9-ethyl-9,l0-dihydroethanoanthmcene'llalzfdlcarboxlmlde;9,10-ethanoanthracene-ll-n-propyl-l1,12-dicarboximide 'Z'PY YD-PJOd1hydr0-9,10-ethanoanthracene-l 1,12-d1carbox1m1de. 0.02 mole ofN-amino-Z-nitro-9-ethyl-9,IO-dihydro- Y -Y9,10-ethanoanthracene-ll-n-propyl 11,12-dicarboximide anthracene'l 1,lz-dicafboXimidein 100 ml. of 10% acetic acid and 3 g. of 10% palladiumY -P P Y Y J on charcoal is shaken with hydrogen for three hours unl lila fi til about 0.06 moles of hydrogen have been absorbed. The P P Q-Q yethanoanthlficenecatalyst is filtered out, the product is precipitatedby add- ILIZ'dICaFbOXImIdE- ing an excess of 10% sodium hydroxide and isrecrystal- Y y 0 e hanoanthracene-ll, lj ed fro ethanol.l2-d1carboximido)pyridinium salt.

The compounds of this invention can be administered [P- Yethanoanthfacene-l1,12-diwith phar m-aceuti'cally acceptable inertcarriers in a wide )P Y f y ni In Sal variety of oral or parenteral unitdosage forms containing Y ['P-( y 09,10 ethanoanthraCene-ll, 25, 100,250 or 500 mg. of active ingredients for thell-dlcarboXlmidwphenylldimethyl n m alt. symptomatic adjustment of thedosage, or in admixture Y Y (9,10 y ethanowith other active compounds.In the case of the comanthracene'l1,lz-dicafboximido)Piperidinium de.pounds encompassed by Formula II intraperitoneal adi 'd yethanoanthraministration is preferred The dosage range for humanscene-l'l,lZ-drcarboxrmrdo)-1-ethy1piperidinium bromide. ranges between0.1 to 3 grams per day depending upon p Y P' Y n an'thracenevariousfactors such as the general condition of the patient1hlz'dlcarboxlmldo)Phenyllmethylammonium alt.

and the severity of the condition to be managed. It is found generallythat when the compounds are adminis- 7 (R f on f ll i page) 3,377,353 78 References Cited OTHER REFERENCES Copa: Chem. A-bst., v01. 55, 123741)(1961).

UNITED STATES PATENTS K1tam0g1 et aL, Chem. Abst., vol. 60, 41130(1964). 3,123,618 3/1964 Schumann et a1 260-295 ..294 7 5 JOHN D.RANDOLPH, Primary Examiner.

WALTER A. MODANCE, Examiner.

A. Dv SPEVACK, Assistant Examiner.

3,135,749 6/1964 cumon et a1 26 FOREIGN PATENTS.

38/17;827 9/1963 Japan.

1. A COMPOUND REPRESENTED BY THE FORMULA: